pharmaceuticalsvolume 100 A

A review of humAn cArcinogens

this publication represents the views and expert opinions of an iarc Working Group on the

evaluation of carcinogenic risks to humans, which met in lyon, 14-21 October 2008

lyon, france - 2012

iArc monogrAphs on the evAluAtion

of cArcinogenic risks to humAns

PHENACETINPhenacetin was considered by previous IARC Working Groups in 1976 and 1980 (IARC, 1977, 1980). Analgesic mixtures containing phenacetin were considered by a previous IARC Working Group in 1987 (IARC, 1987a). Since that time, new data have become available, these have been incorporated into the Monograph, and taken into consideration in the present evaluation.

1. Exposure Data

1.1 Identification of the agent

Chem. Abstr. Serv. Reg. No.: 62-44-2Chem. Abstr. Name: Acetamide, N-(4-eth-oxyphenyl)-IUPAC Systematic Name: N-(4-Ethoxyphe-nyl)acetamideSynonyms: Aceto-4-phenetidine; acetophe-netidin; acetophenetidine; acetophenetin; acetphenetidin; 4-(acetylamino)phenetole; N-acetyl-4-ethoxyaniline; N-acetyl-p-ethoxyaniline; N-acetyl-p-phenetidine; 4-ethoxyacetanilide; 4′-ethoxyacetanilide; p-ethoxyacetanilide; N-(4-ethoxyphenyl)acetamide; MironalDescription: Slightly bitter, crystalline scales or powder (O’Neil, 2006)

1.1.1 Structural and molecular formulae, and relative molecular mass

N CH3

OOH3C

H

C10H13NO2

Relative molecular mass: 179.22

1.2 Use of the agent

1.2.1 Indications

Phenacetin was used as an analgesic and fever-reducing drug in both human and veterinary medicine for many years. It was introduced into therapy in 1887 and was extensively used in anal-gesic mixtures until it was implicated in kidney disease (nephropathy) due to abuse of analgesics. Phenacetin also was once used as a stabilizer for hydrogen peroxide in hair-bleaching prepara-tions (IARC, 1980; Nugent & Hall, 2000).

377

IARC MONOGRAPHS – 100A

1.2.2 Dosage

Analgesic mixtures containing phenacetin were previously marketed as tablets or capsules containing between 150 and 300 mg phenacetin. Common combinations were: 150  mg phen-acetin, 230 mg aspirin, and 15 or 30 mg caffeine; or 150  mg phenacetin, 230  mg aspirin, 30  mg caffeine, and 8, 15, 30, or 60 mg codeine phos-phate. Phenacetin alone was also available in 250 and 300 mg doses as tablets, and up to 500 mg doses as powder. The usual dose was 300  mg 4–6 times per day, and the daily dose was not to exceed 2 g (IARC, 1977, 1980).

1.2.3 Trends in use

Phenacetin was withdrawn from the market in Canada in 1978, in the United Kingdom in 1980 (IARC, 1980), and in the Unites States of America in 1983 (FDA, 1999).

Over-the-counter sales of phenacetin-containing analgesics have been legally prohib-ited in most countries. For example, in Australia, analgesic mixtures containing phenacetin were legally banned in 1977 (Michielsen & de Schepper, 2001), in Belgium in 1987 (Michielsen & de Schepper, 2001), in Germany in 1986 (Schwarz et al., 1999), and in Denmark in 1985 (Nørgaard & Jensen, 1990). In the Czech Republic, anal-gesic mixtures containing phenacetin were recently removed from the market. They are still available in Hungary under the trade names Antineuralgica and Dolor (Sweetman, 2008). Phenacetin was withdrawn from many analgesic mixtures long before the legal ban in several countries.

2. Cancer in Humans

2.1 Case reports

Many case reports of renal pelvic and other urothelial tumours in patients who used large amounts of phenacetin-containing analgesics have been recorded (IARC, 1987a).

2.2 Case–control studies

Case–control studies have been used almost exclusively to examine the association between consumption of analgesics and various cancers of the urinary tract. In all of the studies avail-able to the Working Group, the cumulative use of groups of pharmaceuticals was assessed by asking study subjects about their retrospective use. In most epidemiological studies reviewed, it was rather difficult to estimate the effect of phenacetin separately from the effect of other analgesics, as various pain-relieving substances are often combined in the same pharmaceutical product.

See Table 2.1

2.2.1 Cancer of the renal pelvis and ureter

Small-to-medium-sized case–control studies from Australia (McCredie et al., 1982, 1983a, b; McCredie & Stewart, 1988), Denmark (Jensen et al., 1989) and Germany (Pommer et al., 1999) all suggested a moderate-to-strong association between the regular use of analgesics containing phenacetin and tumours of the renal pelvis (rela-tive risk, 4.2–6.0).

This relationship was also tested in three larger case–control studies, one from Australia (McCredie et al., 1993), and two from the USA (Ross et al., 1989; Linet et al., 1995), each of which included some 150–500 patients with cancers of the renal pelvis and ureter. The Australian study, which included information on subjects’ cumu-lative intake of phenacetin before 1987, showe a

378

Phenacetin

379

Tabl

e 2.

1 C

ase–

cont

rol s

tudi

es o

f can

cer o

f the

urin

ary

trac

t and

con

sum

ptio

n of

ana

lges

ic m

ixtu

res

cont

aini

ng

phen

acet

in

Ref

eren

ce,

stud

y lo

catio

n an

d pe

riod

Org

an

site

(IC

D

code

)

Cha

ract

eris

tics

of c

ases

Cha

ract

eris

tics

of c

ontr

ols

Exp

osur

e as

sess

men

tE

xpos

ure

cate

gori

esN

o. o

f ex

pose

d ca

ses

Rel

ativ

e ri

sk (9

5%

CI)

Adj

ustm

ent

for p

oten

tial

conf

ound

ers

Com

men

ts

Can

cer o

f the

rena

l pel

vis a

nd u

rete

rM

cCre

die

et

al. (

1982

) N

ew S

outh

W

ales

, A

ustr

alia

, 19

77–8

0

Rena

l pe

lvis

(I

CD

-8:

189.

1)

27 m

en, 4

0 w

omen

fr

om th

e N

ew

Sout

h W

ales

C

ance

r Reg

istr

y an

d fr

om 3

Sy

dney

hos

pita

ls;

case

s con

firm

ed

hist

olog

ical

ly

180

volu

ntee

rs,

frie

nds a

nd

rela

tives

In-p

erso

n st

ruct

ured

in

terv

iew

un

dert

aken

at

hosp

ital o

r at

hom

e

Life

time c

onsu

mpt

ion

of p

hena

cetin

-co

ntai

ning

ana

lges

ics (

kg) i

n w

omen

Age

and

use

of

othe

r typ

es o

f an

alge

sics.

Not

ad

just

ed fo

r sm

okin

g

Resp

onse

rate

s no

t giv

en, r

ates

of

rena

l pel

vis

canc

er in

men

no

t giv

en

No

late

ncy:

No

use

(< 0

.1)N

R1

(ref

)

≥ 0.

1N

R2.

4 (1

.0–6

.0)

5-ye

ar

late

ncy:

No

use

(< 0

.1)N

R1

(ref

)

≥ 0.

1N

R4.

1 (1

.8–9

.2)

McC

redi

e et

al

. (19

88)

New

Sou

th

Wal

es,

Aus

tral

ia,

1980

–82

Rena

l pe

lvis

(I

CD

-8:

189.

1)

73 (3

1 m

en, 4

2 w

omen

) fro

m th

e N

ew S

outh

Wal

es

Cen

tral

Can

cer

Regi

stry

688

(307

men

, 38

1 w

omen

) po

pula

tion-

base

d co

ntro

ls 50

-yr-

old

or a

bove

sele

cted

at

rand

om fr

om

the

New

Sou

th

Wal

es e

lect

ion

rolls

198

0–81

; re

spon

se ra

te 7

2%

Stan

dard

ized

qu

estio

nnai

re

mai

led

to

part

icip

ants

Life

time c

onsu

mpt

ion

of p

hena

cetin

(kg)

Sex,

pa

race

tam

ol

use,

smok

ing

Resp

onse

rate

for

case

s not

giv

en.

No

use

defin

ed

as li

fetim

e co

nsum

ptio

n < 

0.1 

kg u

p til

l the

dat

e of

di

agno

sis o

r th

e eq

uiva

lent

da

te fo

r con

trol

. Ph

enac

etin

al

way

s in

prep

arat

ions

co

ntai

ning

as

piri

n an

d ei

ther

caff

eine

or

code

ine

No

use

[37]

1 (r

ef)

≥ 0.

1N

C5.

7 (3

.2–1

0.0)

≥ 1.

0[2

4]7.9

(4.6

–13.

8)

IARC MONOGRAPHS – 100A

380

Ref

eren

ce,

stud

y lo

catio

n an

d pe

riod

Org

an

site

(IC

D

code

)

Cha

ract

eris

tics

of c

ases

Cha

ract

eris

tics

of c

ontr

ols

Exp

osur

e as

sess

men

tE

xpos

ure

cate

gori

esN

o. o

f ex

pose

d ca

ses

Rel

ativ

e ri

sk (9

5%

CI)

Adj

ustm

ent

for p

oten

tial

conf

ound

ers

Com

men

ts

McC

redi

e et

al

. (19

83a;

19

83b)

19

80–8

2

Ure

ter

(IC

D-8

: 18

9.2)

36 m

ales

from

the

New

Sou

th W

ales

C

entr

al C

ance

r Re

gist

ry

307

mal

e po

pula

tion-

base

d co

ntro

ls 50

-yr-

old

or a

bove

sele

cted

at

rand

om fr

om

the

New

Sou

th

Wal

es e

lect

ion

rolls

198

0–81

; re

spon

se ra

te 7

2%

No

use

NR

1 (r

ef)

Re-a

naly

sis o

f th

e or

igin

al d

ata

≥ 0.

1N

R0.

7 (0

.3–2

.2)

≥ 1.

0N

R1.

2 (0

.5–3

.0)

McL

augh

lin

et a

l. (1

983)

M

inne

apol

is-

St. P

aul

met

ropo

litan

ar

ea, U

SA,

1974

–79

Rena

l pe

lvis

(I

CD

-8:

189.

1)

74 (5

0 m

en, 2

4 w

omen

) fro

m th

e M

inne

apol

is-S

t. Pa

ul m

etro

polit

an

area

30–

79-y

r-ol

d;

case

s con

firm

ed

hist

olog

ical

ly; 9

5%

resp

onse

rate

697

(428

men

, 269

w

omen

) sel

ecte

d at

rand

om

from

tele

phon

e lis

tings

, fro

m

files

of t

he H

ealth

C

are

Fina

ncin

g A

dmin

istr

atio

n an

d fr

om d

eath

ce

rtifi

cate

list

ings

; re

spon

se ra

te 9

4%

In-p

erso

n st

ruct

ured

in

terv

iew

of

part

icip

ants

or

nex

t-of

-kin

un

dert

aken

at

hom

e

Use

of p

hena

cetin

- or a

ceta

min

ophe

n-co

ntai

ning

ana

lges

ics

Age

and

ci

gare

tte

smok

ing

No

use

defin

ed

as: n

ever

use

d ph

enac

etin

- or

para

ceta

mol

-co

ntai

ning

dr

ugs r

egul

arly

fo

r ≥ 1

 mo.

Of

7 ca

ses w

ho

wer

e lo

ng-t

erm

us

ers,

1 us

ed

para

ceta

mol

co

mpo

unds

onl

y

Men

:N

o us

e23

1 (r

ef)

Non

-reg

ular

us

e21

0.9

(0.4

–1.8

)

Regu

lar u

se,

≤ 36

mo

20.

7 (0

.1–3

.9)

Regu

lar u

se,

> 36

mo

43.

9 (0

.7–2

0.4)

Wom

en:

No

use

91

(ref

)N

on-r

egul

ar

use

101.

4 (0

.5–4

.2)

Regu

lar u

se,

≤ 36

mo

22.

3 (0

.2–1

9.7)

Regu

lar u

se,

> 36

mo

33.

7 (0

.5–2

4.7)

Tabl

e 2.

1 (c

ontin

ued)

Phenacetin

381

Ref

eren

ce,

stud

y lo

catio

n an

d pe

riod

Org

an

site

(IC

D

code

)

Cha

ract

eris

tics

of c

ases

Cha

ract

eris

tics

of c

ontr

ols

Exp

osur

e as

sess

men

tE

xpos

ure

cate

gori

esN

o. o

f ex

pose

d ca

ses

Rel

ativ

e ri

sk (9

5%

CI)

Adj

ustm

ent

for p

oten

tial

conf

ound

ers

Com

men

ts

Jens

en e

t al.

(198

9)

Cop

enha

gen,

D

enm

ark,

19

79–8

2

Rena

l pe

lvis

and

ur

eter

96 (6

0 m

en, 3

6 w

omen

) not

ified

di

rect

ly fr

om 2

7 ho

spita

l uni

ts o

f Ea

ster

n D

enm

ark;

re

spon

se ra

te 9

9%

288

(180

men

, 108

w

omen

) sel

ecte

d at

rand

om fr

om

med

ical

or

surg

ical

war

ds

mat

ched

for

hosp

ital,

sex

and

age

in 5

-yr

age

grou

ps;

patie

nts w

ith

urin

ary-

trac

t- an

d sm

okin

g-re

late

d di

seas

es w

ere

not

elig

ible

; res

pons

e ra

te 9

9%

In-p

erso

n st

ruct

ured

in

terv

iew

un

dert

aken

at

hosp

ital

Life

time c

onsu

mpt

ion

of p

hena

cetin

(g)

Use

of a

nalg

esic

s m

easu

red

up

until

5 y

r bef

ore

inte

rvie

w. Th

e ‘n

o us

e’ le

vel n

ot

clea

rly d

efine

d.

The

influ

ence

of

phen

acet

in a

nd

aspi

rin

coul

d no

t be

sepa

rate

d in

the

anal

ysis

. In

com

plet

e ad

just

men

t for

sm

okin

g ha

bits

(<

 10

vs ≥

 10

pack

-yr)

Men

Age

Nev

er u

sed

anal

gesic

s31

1 (r

ef)

Ever

use

d ph

enac

etin

133.

9 (1

.7–9

.1)

1–74

96

3.1

(1.0

–9.6

)≥7

505

9.1

(2.2

–38)

Wom

enN

ever

use

of

anal

gesic

s9

1 (r

ef)

Ever

use

d ph

enac

etin

176.

9 (2

.7–1

8)

1–74

94

6.1

(1.5

–26)

≥750

76.

1 (1

.9–2

0)Ev

er u

sed

phen

acet

inA

ge, t

obac

co

smok

ing,

‘h

igh

risk

’ oc

cupa

tions

an

d as

piri

n

Men

122.

4 (0

.9–6

.8)

Wom

en15

4.2

(1.5

–12)

Pom

mer

et a

l. (1

999)

Be

rlin

G

erm

any

1990

–94

Rena

l pe

lvis

and

ur

eter

(I

CD

-9:

189.

1–2)

76 (3

7 m

en,

39 w

omen

) di

agno

sed

in 1

of

8 u

rolo

gica

l de

part

men

ts;

resp

onse

rate

85%

76 su

bjec

ts

sele

cted

at r

ando

m

from

the

cent

ral

inha

bita

nt re

gist

ry

of th

e fo

rmer

W

est B

erlin

are

a in

divi

dual

ly

mat

ched

to c

ase

subj

ect b

y se

x an

d ag

e (±

 2 y

r);

resp

onse

rate

70%

In-p

erso

n st

ruct

ured

in

terv

iew

un

dert

aken

at

hos

pita

l (c

ases

) or a

t pa

rtic

ipan

ts’

hom

e (c

ontr

ols)

No

or ra

re

inta

ke o

f an

alge

sics

311

(ref

)C

urre

nt

smok

ing,

fo

rmer

sm

okin

g,

soci

oeco

nom

ic

stat

us, l

axat

ive

inta

ke

Rare

inta

ke

defin

ed a

s int

ake

of le

ss th

an 1

an

alge

sic d

ose/

mo

Life

time

cons

umpt

ion

of

phen

acet

in

(kg)

≥ 1

71.

8 (0

.2–1

4)

Tabl

e 2.

1 (c

ontin

ued)

IARC MONOGRAPHS – 100A

382

Ref

eren

ce,

stud

y lo

catio

n an

d pe

riod

Org

an

site

(IC

D

code

)

Cha

ract

eris

tics

of c

ases

Cha

ract

eris

tics

of c

ontr

ols

Exp

osur

e as

sess

men

tE

xpos

ure

cate

gori

esN

o. o

f ex

pose

d ca

ses

Rel

ativ

e ri

sk (9

5%

CI)

Adj

ustm

ent

for p

oten

tial

conf

ound

ers

Com

men

ts

McC

redi

e et

al

. (19

93)

New

Sou

th

Wal

es

Aus

tral

ia,

1989

–90

Rena

l pe

lvis

(I

CD

-9:

189.

1)

147

(58

men

, 89

wom

en) i

n ag

e ra

nge

20–7

9-yr

at d

iagn

osis

fr

om a

rapi

d-as

cert

ainm

ent

syst

em a

nd th

e N

ew S

outh

Wal

es

Cen

tral

Can

cer

Regi

stry

; pat

ient

s ha

d to

be

liste

d in

tele

phon

e di

rect

ory

and

able

to

spea

k En

glis

h to

be

incl

uded

; re

spon

se ra

te 8

9%

523

(231

men

, 29

2 w

omen

) fr

eque

ncy-

mat

ch to

cas

es

on a

ge a

nd se

x an

d se

lect

ed a

t ra

ndom

from

the

New

Sou

th W

ales

el

ecto

ral r

olls

; co

ntro

ls ha

d to

be

liste

d in

tele

phon

e di

rect

ory

and

able

to

spea

k En

glis

h to

be

sele

cted

; re

spon

se ra

te 7

4%

Stru

ctur

ed

inte

rvie

w

unde

rtak

en a

t pa

rtic

ipan

ts’

hom

e or

co

nduc

ted

over

the

tele

phon

e

Phen

acet

in-c

onta

inin

g an

alge

sics

Age

, sex

, ci

gare

tte

smok

ing,

ed

ucat

ion

leve

l, m

etho

d of

inte

rvie

w

The

non-

cons

umer

ca

tego

ry d

efine

d as

per

sons

re

port

ing

taki

ng

anal

gesic

s le

ss th

an 2

0 tim

es in

thei

r lif

etim

e. In

take

of

ana

lges

ics

incl

uded

in

anal

ysis

up

till

end

of 1

986.

Ph

enac

etin

al

way

s in

prep

arat

ions

co

ntai

ning

as

piri

n pl

us

eith

er c

affei

ne o

r co

dein

e

Non

-co

nsum

ers

761

(ref

)

Any

7012

.2 (6

.8–2

2)To

tal u

se p

re-1

987

(kg)

≤ 2.

0412

5.2

(2.2

–12)

Age

, sex

, ci

gare

tte

smok

ing,

ed

ucat

ion

leve

l, m

etho

d of

inte

rvie

w,

para

ceta

mol

in

any

form

2.04

–6.8

7≥ 

6.88

16 428.

3 (3

.4–2

1)18

.5 (8

.7–3

9)Te

st fo

r tr

end:

P 

= 0.

019

Ross

et a

l. (1

989)

Lo

s Ang

eles

C

ount

y U

SA,

1978

–82

Rena

l pe

lvis

and

ur

eter

187

(127

men

, 60

wom

en) s

elec

ted

from

the

Los

Ang

eles

Cou

nty

Can

cer R

egis

try,

diag

nose

d un

der

age

75; r

espo

nse

rate

80%

187

neig

hbou

rhoo

d co

ntro

ls se

lect

ed

at ra

ndom

an

d m

atch

ed

indi

vidu

ally

to

case

s by

sex,

dat

e of

bir

th (±

 5 y

r),

and

race

Stru

ctur

ed

inte

rvie

w o

ver

the

tele

phon

e

Phen

acet

in-

cont

aini

ng

anal

gesic

s

Age

, sex

, rac

eRe

spon

se ra

te

not g

iven

for

cont

rol s

ubje

cts.

Use

of a

nalg

esic

m

easu

red

up

until

dat

e of

di

agno

sis o

r eq

uiva

lent

dat

e fo

r con

trol

. Re

fere

nce

cate

gory

defi

ned

as ‘n

o us

e or

use

fe

wer

than

30

times

in a

yr’.

N

on-p

resc

ript

ion

com

poun

ds in

fo

cus o

f the

stud

y

> 30

d/y

r> 

30

cons

ecut

ive

d

11 71.

1 (P

 = 0

.83)

1.4

(P =

 0.5

6)

Tabl

e 2.

1 (c

ontin

ued)

Phenacetin

383

Ref

eren

ce,

stud

y lo

catio

n an

d pe

riod

Org

an

site

(IC

D

code

)

Cha

ract

eris

tics

of c

ases

Cha

ract

eris

tics

of c

ontr

ols

Exp

osur

e as

sess

men

tE

xpos

ure

cate

gori

esN

o. o

f ex

pose

d ca

ses

Rel

ativ

e ri

sk (9

5%

CI)

Adj

ustm

ent

for p

oten

tial

conf

ound

ers

Com

men

ts

Line

t et a

l. (1

995)

M

ultic

entr

e st

udy

USA

, 19

83–8

6

Rena

l pe

lvis

and

ur

eter

502

(331

men

, 17

1 w

omen

) C

auca

sian

s in

age

rang

e 20

–79-

yr-

old

at d

iagn

osis

se

lect

ed fr

om

popu

latio

n-ba

sed

canc

er re

gist

ries

in

New

Jers

ey,

Iow

a an

d Lo

s A

ngel

es; r

espo

nse

rate

72%

; cas

es

confi

rmed

hi

stol

ogic

ally

496

(315

men

, 11

5 w

omen

) fr

eque

ncy-

mat

ched

to c

ases

by

sex

and

5-yr

ag

e gr

oups

and

se

lect

ed u

sing

ra

ndom

-dig

it di

allin

g (u

nder

ag

e 65

) or t

aken

fr

om th

e fil

es

of H

ealth

Car

e Fi

nanc

ing

Adm

inis

trat

ion

(65-

yr-o

ld o

r ab

ove)

; res

pons

e ra

te 6

6%

In-p

erso

n st

ruct

ured

in

terv

iew

in

subj

ects

’ hom

e

Non

e or

no

regu

lar u

se

of a

nalg

esic

s

385

1 (r

ef)

Age

, sex

, ge

ogra

phic

ar

ea, c

igar

ette

sm

okin

g

Regu

lar u

se

defin

ed a

s at l

east

2

or m

ore

times

/w

k fo

r at l

east

1

mo.

U

se o

f ana

lges

ics

mea

sure

d up

un

til 5

 yr b

efor

e in

terv

iew

. N

on-p

resc

ript

ive

as w

ell a

s pr

escr

iptiv

e an

alge

sics

incl

uded

. Lo

w p

ropo

rtio

n of

regu

lar

anal

gesic

use

rs

and

lack

of

“phe

nace

tin

abus

ers.”

Ph

enac

etin

rare

ly

avai

labl

e as

a

sing

le a

gent

Regu

lar

use

of

phen

acet

in-

cont

aini

ng

anal

gesic

s

300.

8 (0

.5–1

.4)

Dur

atio

n of

use

of p

hena

cetin

-con

tain

ing

anal

gesic

s (yr

)≤ 

412

0.7

(0.3

–1.6

)5–

96

0.8

(0.3

–2.7

)≥ 

1011

0.9

(0.4

–2.2

)Li

fetim

e con

sum

ptio

n of

phe

nace

tin (k

g)≤ 

1.0

210.

8 (0

.4–1

.6)

> 1.

09

0.8

(0.3

–2.1)

Can

cer o

f the

kid

ney

Mc

Laug

hlin

et

al.

(199

2)

Shan

ghai

, C

hina

, 19

87–8

9

Rena

l cel

l ca

rcin

oma

(IC

D-9

: 18

9.0)

154

(90

men

, 64

wom

en)

in a

ge ra

nge

35–7

4-yr

-old

from

a

popu

latio

n-ba

sed

canc

er

regi

stry

cov

erin

g ur

ban

Shan

ghai

; re

spon

se ra

te 8

7%;

case

s con

firm

ed

hist

olog

ical

ly

157

(91

men

, 66

wom

en) s

elec

ted

at ra

ndom

from

th

e Sh

angh

ai

Resid

ent R

egis

try

and

freq

uenc

y m

atch

ed o

n se

x an

d ag

e; re

spon

se

rate

100

%

In-p

erso

n st

ruct

ured

in

terv

iew

of

part

icip

ants

at

hom

e

No

or n

on-

regu

lar u

se

of a

nalg

esic

s

NR

1 (r

ef)

Age

, sex

, ed

ucat

ion,

BM

I, sm

okin

g

Regu

lar

cons

umpt

ion

of a

nalg

esic

s de

fined

as a

t lea

st

twic

e/w

k fo

r 2

wk

or lo

nger

; us

e of

ana

lges

ics

unco

mm

on in

st

udy

area

Use

of

phen

acet

in-

cont

aini

ng

anal

gesic

sRe

gula

r use

NR

2.3

(0.7

–7.0

)

Tabl

e 2.

1 (c

ontin

ued)

IARC MONOGRAPHS – 100A

384

Ref

eren

ce,

stud

y lo

catio

n an

d pe

riod

Org

an

site

(IC

D

code

)

Cha

ract

eris

tics

of c

ases

Cha

ract

eris

tics

of c

ontr

ols

Exp

osur

e as

sess

men

tE

xpos

ure

cate

gori

esN

o. o

f ex

pose

d ca

ses

Rel

ativ

e ri

sk (9

5%

CI)

Adj

ustm

ent

for p

oten

tial

conf

ound

ers

Com

men

ts

Kre

iger

et a

l. (1

993)

Pr

ovin

ce

of O

ntar

io,

Can

ada,

19

86–8

7

Rena

l cel

l ca

rcin

oma

(IC

D-9

: 18

9.0)

513

(312

men

, 20

1 w

omen

) in

age

rang

e 25

–69-

yr-o

ld

from

the

Ont

ario

C

ance

r Reg

istr

y;

resp

onse

rate

81%

; ca

ses c

onfir

med

hi

stol

ogic

ally

1381

(664

men

, 70

5 w

omen

) se

lect

ed a

t ran

dom

fr

om th

e 19

86 a

nd

1987

Enu

mer

atio

n Re

cord

s of

Ont

ario

and

fr

eque

ncy-

mat

ched

to c

ase

grou

p on

age

, sex

an

d ge

ogra

phic

re

gion

of

resid

ence

Stan

dard

ized

qu

estio

nnai

re

mai

led

to

part

icip

ants

Use

of p

hena

cetin

or p

hena

cetin

-co

ntai

ning

ana

lges

ics

Age

, sm

okin

g,

BMI

Expo

sure

to

anal

gesic

s was

de

fined

as u

se

at le

ast e

very

ot

her d

ay fo

r one

m

onth

or m

ore

befo

re 1

980;

ver

y fe

w in

divi

dual

s w

ere

clas

sifie

d as

ana

lges

ic

user

s; on

ly 5

m

ale

case

s and

3

fem

ale

case

s eve

r ex

pose

d

Men

No

phen

acet

in

or

para

ceta

mol

265

1 (r

ef)

Phen

acet

in

only

22.

5 (0

.3–1

8.5)

Any

ph

enac

etin

51.

7 (0

.5–5

.9)

Wom

enN

o ph

enac

etin

or

pa

race

tam

ol

166

1 (r

ef)

Phen

acet

in

only

31.

8 (0

.5–7

.3)

Any

ph

enac

etin

30.

8 (0

.2–2

.7)

Cho

w e

t al.

(199

4)

Min

neso

ta

USA

, 19

88–9

0

Rena

l cel

l ca

rcin

oma

(IC

D-9

: 18

9.0)

440

in a

ge ra

nge

20–7

9-yr

-old

from

th

e M

inne

sota

st

ate

canc

er

surv

eilla

nce

syst

em; r

espo

nse

rate

87%

; cas

es

confi

rmed

hi

stol

ogic

ally

707

freq

uenc

y-

mat

ched

to c

ases

by

sex

and

5-yr

ag

e gr

oups

and

se

lect

ed u

sing

ra

ndom

-dig

it di

allin

g (u

nder

ag

e 65

) or t

he

files

of H

ealth

C

are

Fina

ncin

g A

dmin

istr

atio

n (6

5-yr

-old

or

abov

e); r

espo

nse

rate

≈85

%

In-p

erso

n st

ruct

ured

in

terv

iew

of

part

icip

ants

or

nex

t-of

-kin

(fo

r dec

ease

d pa

tient

s) a

t th

eir h

omes

Life

time c

onsu

mpt

ion

of p

hena

cetin

(kg)

Age

, sm

okin

g,

quar

tile

of

BMI

Regu

lar u

se o

f an

alge

sics w

ere

defin

ed a

s at l

east

2

or m

ore

times

/w

k fo

r 1 m

o be

fore

198

7.

Ove

rlapp

ing

at

leas

t in

part

with

th

e in

tern

atio

nal

stud

y de

scri

bed

belo

w

No

or n

on-

regu

lar u

se

of a

nalg

esic

s

195

1 (r

ef)

Men

< 0.

12

0.4

(0.1

–1.9

)0.

1–1

10.

1 (0

.0–0

.8)

> 1

30.

6 (0

.2–2

.6)

No

or n

on-

regu

lar u

se

of a

nalg

esic

s

101

1 (r

ef)

Wom

en< 

0.1

20.

9 (0

.1–5

.8)

0.1–

12

0.6

(0.1

–3.5

)

> 1

20.

4 (0

.1–2

.3)

Tabl

e 2.

1 (c

ontin

ued)

Phenacetin

385

Ref

eren

ce,

stud

y lo

catio

n an

d pe

riod

Org

an

site

(IC

D

code

)

Cha

ract

eris

tics

of c

ases

Cha

ract

eris

tics

of c

ontr

ols

Exp

osur

e as

sess

men

tE

xpos

ure

cate

gori

esN

o. o

f ex

pose

d ca

ses

Rel

ativ

e ri

sk (9

5%

CI)

Adj

ustm

ent

for p

oten

tial

conf

ound

ers

Com

men

ts

McC

redi

e et

al

. (19

95)

Inte

rnat

iona

l m

ultic

entr

e st

udy:

A

ustr

alia

, D

enm

ark,

G

erm

any,

Swed

en

and

USA

, 19

89–9

1

Rena

l cel

l ca

rcin

oma

1732

in a

ge

rang

e 20

–79-

yr-

old

(20–

75 in

G

erm

an c

entr

e)

recr

uite

d th

roug

h a

natio

nally

m

odifi

ed ra

pid

asce

rtai

nmen

t sy

stem

(all

stud

y ce

ntre

s)

in c

ombi

natio

n w

ith th

e fil

es o

f po

pula

tion-

base

d ca

ncer

regi

stri

es

(in A

ustr

alia

, D

enm

ark,

Sw

eden

an

d th

e U

SA);

over

all r

espo

nse

rate

(inc

ludi

ng

non-

resp

onse

due

to

dea

th) 7

2.3%

; ca

ses c

onfir

med

hi

stol

ogic

ally

2309

freq

uenc

y-

mat

ched

to c

ases

by

age

and

sex

and

sele

cted

by

cent

re-s

peci

fic

met

hods

from

the

sam

e st

udy

base

as

the

case

gro

up;

resp

onse

rate

74

.7%

In-p

erso

n st

ruct

ured

in

terv

iew

at

part

icip

ants

’ ho

me

Life

time c

onsu

mpt

ion

of p

hena

cetin

(kg)

Cen

tre,

age

, se

x (w

here

ap

prop

riat

e),

BMI,

pack

-yr

of to

bacc

o

Refe

renc

e gr

oup

was

com

pose

d of

subj

ects

w

ho –

bef

ore

1987

– n

ever

to

ok a

nalg

esic

s, w

ere

not r

egul

ar

take

rs (l

ess t

han

twic

e/w

k), o

r to

ok a

life

time

tota

l of <

 0.1

 kg

of a

ll ty

pes

of a

nalg

esic

s co

mbi

ned;

lack

of

ass

ocia

tion

not a

ltere

d by

rest

rict

ing

anal

gesic

use

to

that

whi

ch

occu

rred

5 o

r 10

yr b

efor

e cu

toff

data

(198

7)

Men

and

w

omen

Refe

renc

e gr

oup

1313

1 (r

ef)

< 0.

131

0.8

(0.5

–1.3

)≥ 

0.1

971.

1 (0

.8–1

.4)

0.1–

1.0

510.

9 (0

.6–1

.3)

1.1–

5.0

361.

6 (0

.9–2

.6)

> 5.

010

0.9

(0.4

–2.1)

Men

< 0.

114

0.6

(0.3

–1.2

)≥ 

0.1

460.

9 (0

.6–1

.4)

0.1–

1.0

250.

7 (0

.4–1

.2)

1.1–

5.0

161.

3 (0

.6–2

.7)

> 5.

05

2.6

(0.5

–14.

2)W

omen

< 0.

117

1.1

(0.6

–2.3

)≥ 

0.1

511.

4 (0

.9–2

.1)0.

1–1.

026

1.3

(0.7

–2.3

)1.

1–5.

020

2.1

(1.0

–4.4

)> 

5.0

50.

6 (0

.2–1

.8)

Tabl

e 2.

1 (c

ontin

ued)

IARC MONOGRAPHS – 100A

386

Ref

eren

ce,

stud

y lo

catio

n an

d pe

riod

Org

an

site

(IC

D

code

)

Cha

ract

eris

tics

of c

ases

Cha

ract

eris

tics

of c

ontr

ols

Exp

osur

e as

sess

men

tE

xpos

ure

cate

gori

esN

o. o

f ex

pose

d ca

ses

Rel

ativ

e ri

sk (9

5%

CI)

Adj

ustm

ent

for p

oten

tial

conf

ound

ers

Com

men

ts

Gag

o-D

omin

guez

et

al.

(199

9),

Los A

ngel

es,

USA

, 19

86–9

4

Rena

l cel

l ca

ncer

1204

(781

men

, 42

3 w

omen

) no

n-A

sian

s in

age

rang

e 25

–74-

yr-

old

from

the

Los

Ang

eles

Cou

nty

Can

cer R

egis

try;

re

spon

se ra

te

(incl

udin

g no

n-re

spon

se d

ue

to d

eath

) 74%

; ca

ses c

onfir

med

hi

stol

ogic

ally

1204

non

-Asi

ans

neig

hbou

rhoo

d co

ntro

ls se

lect

ed

at ra

ndom

an

d m

atch

ed

indi

vidu

ally

to

case

s by

sex,

dat

e of

bir

th (±

 5 y

r),

race

; res

pons

e ra

te

not g

iven

In-p

erso

n st

ruct

ured

in

terv

iew

at

part

icip

ants

’ ho

me

No

or

irre

gula

r use

of

ana

lges

ics

616

1 (r

ef)

Leve

l of

educ

atio

n,

obes

ity,

hist

ory

of

hype

rten

sion,

sm

okin

g (y

es/n

o),

regu

lar u

se o

f am

feta

min

es

Expo

sure

in

form

atio

n re

ques

ted

up

to 2

 yr b

efor

e th

e da

te o

f di

agno

sis f

or

case

s and

at t

he

equi

vale

nt d

ate

for t

he m

atch

ed

cont

rol.

No

use

was

defi

ned

as

an in

take

less

th

an 2

0 tim

es

in a

life

time;

ir

regu

lar u

se w

as

defin

ed a

s int

ake

of a

nalg

esic

s le

ss th

an tw

ice/

wk.

Equ

ally

in

crea

sed

risk

s w

ere

seen

for

othe

r typ

es o

f an

alge

sics,

i.e.

aspi

rin,

non

-as

piri

n N

SAID

s, an

d pa

race

tam

ol

Regu

lar

use

of

phen

acet

in

861.

9 (1

.3–2

.7)

Max

imum

w

eekl

y do

se

(g)

< 2

2– <

 44–

< 8

41 22 20

1.3

(0.8

–2.2

)4.

1 (1

.5–1

0.8)

2.3

(1.0

–5.0

)

BMI,

body

mas

s ind

ex; d

, day

or d

ays;

mo,

mon

th o

r mon

ths;

NR

, not

repo

rted

; NSA

ID, n

on-s

tero

idal

ant

i-infl

amm

ator

y dr

ug; r

ef.,

refe

renc

e; v

s, ve

rsus

; wk,

wee

k or

wee

ks; y

r, ye

ar o

r ye

ars

Tabl

e 2.

1 (c

ontin

ued)

Phenacetin

highly increased relative risk of cancers of the renal pelvis and ureter associated with regular use of phenacetin-containing preparations, and a strong, statistically significant dose–response relationship of increasing risk with increasing consumption of phenacetin (McCredie et al., 1993). In the study area (New South Wales), phenacetin was banned in 1979 from all prepa-rations but was commonly used as an analgesic before that year. The Californian cancer-registry-based study (Ross et al., 1989), including 187 patients with tumours of the renal pelvis and ureter, found a non-significant increased risk for these tumour types associated with heavy use of phenacetin-containing preparations. In the second study from the USA, Linet et al., (1995) did not find a positive association between the use of phenacetin and tumours of the renal pelvis and ureter, and no indication of a positive trend in risk estimates with increasing duration of use or increasing cumulative dose of phenacetin-containing preparations. This apparent lack of association was ascribed by the authors to the fact that phenacetin products had been off the US market for a decade or more when the patients were diagnosed during 1983–87, and that the study revealed a low prevalence of regular users (6–7%) with an apparent lack of any phenacetin abusers.

In the only study in which tumours of the ureter were analysed separately (McCredie & Stewart, 1988), the use of phenacetin was not asso-ciated with an increased incidence of tumours of the ureter. [The Working Group noted that the statistical power of the study was limited.]

2.2.2 Cancer of the kidney parenchyma

Two early case–control studies from the USA and Australia, which included kidney cancer patients diagnosed in the late 1970s and early 1980s, i.e. in the decade following the withdrawal of phenacetin from these markets, reported an increased risk of kidney cancer among regular

users of phenacetin-containing preparations (McLaughlin et al., 1984; McCredie et al., 1988). However, the US study findings were not statis-tically significant, and the Australian study did not show any positive trend in risk by increasing cumulative intake of phenacetin.

Three further case–control studies from the USA, Canada and the People’s Republic of China with recruitment of patients with renal cell cancer diagnosed in the late 1980s did not report signifi-cant associations with use of phenacetin, even in cumulative doses of more than 1 kg (McLaughlin et al., 1992; Kreiger et al., 1993; Chow et al., 1994). Similarly, a large international multicentre case–control study from six well defined geographic areas in Australia, Denmark, Germany, Sweden, and the USA did not link renal cell cancer with consumption of phenacetin-containing prepara-tions (McCredie et al., 1995).

In a large case–control study from California, a statistically significant elevation in risk of renal cell cancer was associated with use of each of four chemical classes of analgesics included in the analysis (Gago-Dominguez et al., 1999). However, no clear increase in risk was observed even with an increase in maximum weekly intake doses of phenacetin.

2.2.3 Cancer of the urinary bladder

Two small case–control studies from Australia (McCredie et al., 1988) and one study from the USA (Piper et al., 1986), with recruit-ment of bladder cancer patients during the late 1970s and early 1980s, reported a positive asso-ciation with use of phenacetin-containing anal-gesics. In the US study, heavy use, defined as daily use of phenacetin-containing analgesics, was associated with a non-significant increased risk of bladder cancer; in the Australian study, lifetime use of phenacetin of 0.1 kg or more was associated with a significant 2-fold increased risk.

387

IARC MONOGRAPHS – 100A

In a large study from California (Castelao et al., 2000), any use of phenacetin-containing analgesics was related to a non-significant increase in bladder cancer risk, however, it was associated with a significant increase in relative risk estimates by an increasing cumulative life-time consumption of phenacetin. Furthermore, in a cancer-registry-based case–control study from the USA, risks of bladder cancer were evaluated in association with use of analgesics and anti-inflammatory drugs (Fortuny et al., 2007). Based on information obtained through an in-person interview, the investigators found a significantly increased risk of bladder cancer in association with use of phenacetin-containing analgesics. A positive, statistically significant trend was observed with reported increasing duration of use.

These findings were not corroborated in a medium-sized German case–control study, in which no elevation of the relative risk estimate for bladder cancer was found in subjects with a lifetime consumption of phenacetin of 1  kg or more (Pommer et al., 1999). [The Working Group noted that phenacetin was banned in 1986 from the pharmaceutical market of the Federal Republic of Germany before reunification, and patients included in the study were diagnosed during 1990–94, i.e. less than 10 years after the ban.]

In another large case–control study from Spain (Fortuny et al., 2006), ever use of phen-acetin was slightly, but non-significantly, more prevalent among cases than among controls. [The Working Group noted that in this study, most cases and controls were interviewed more than 10 years after phenacetin-containing prepara-tions were withdrawn from the Spanish market, and few participants only reported use of this compound.]

3. Cancer in Experimental Animals

3.1 Analgesic mixtures containing phenacetin

Phenacetin has been tested in mice and rats by oral administration, alone and in combina-tion with aspirin, caffeine, and/or phenazone. In a study in male and female mice and rats, a mixture of aspirin (50%), phenacetin (46%), and caffeine (4%) was administered in the diet (0.7% or 1.4%) for up to 78 weeks. There was no observed increase in tumour incidence in mice. There was a significant increase in pituitary adenomas and carcinomas, and adrenal pheochromocytomas in treated males, and a small increase (not statis-tically significant) in the incidence of urinary tract tumours in female rats (NCI, 1978; IARC, 1980, 1987b). Male rats treated with phenacetin, phenazone, and caffeine combined developed liver tumours (hepatomas), while phenacetin-alone or in combination with phenazone with or without caffeine slightly increased the incidence of renal cell and renal pelvic tumours combined (Johansson, 1981; IARC, 1987b).

Phenacetin-alone given orally at doses ranging from 0.5–2.5% in the diet caused benign and malignant tumours of the urinary tract in mice and rats of both sexes (Isaka et al. 1979; Nakanishi et al., 1982; Muradian, 1986; IARC, 1987b), and of the nasal cavity in rats of both sexes (Isaka et al. 1979; IARC, 1980, 1987b). In male rats, phenacetin at doses of 2.5% also enhanced the incidence of urinary bladder tumours induced by N-nitrosobutyl-N-(4-hydroxybutyl)amine (IARC 1980, 1987b).

See Table 3.1

388

Phenacetin

389

Tabl

e 3.

1 St

udie

s of

can

cer i

n ex

perim

enta

l ani

mal

s ex

pose

d to

phe

nace

tin o

r ana

lges

ic m

ixtu

res

cont

aini

ng

phen

acet

in

Spec

ies,

str

ain

(sex

) D

urat

ion

Ref

eren

ce

Rou

te

Dos

ing

regi

men

A

nim

als/

grou

p at

sta

rt

Inci

denc

e of

tum

ours

Sign

ificanc

eC

omm

ents

Mou

se, B

6C3F

1 (M

, F)

94 w

k N

CI (

1978

)

Feed

0,

0.7

or 1

.4%

of a

mix

ture

of a

spir

in,

phen

acet

in a

nd c

affei

ne (5

0:46

:4) f

or u

p to

78

 wk,

obs

erve

d fo

r an

addi

tiona

l 16 

wk

50/g

roup

Mal

es:

Lung

(alv

eola

r/br

onch

iola

r ade

nom

as o

r ca

rcin

omas

)–

6/48

in c

ontr

ols,

9/46

fed

0.7%

, 12/

47 fe

d 1.

4%

NS

Hae

mat

opoi

etic

syst

em (l

euka

emia

s or

mal

igna

nt ly

mph

omas

)–

4/48

in c

ontr

ols,

7/48

fed

0.7%

, 4/4

8 fe

d 1.

4%

NS

Live

r (he

pato

cellu

lar c

arci

nom

as)–

7/

48 in

con

trol

s, 11

/46

fed

0.7%

, 6/4

7 fe

d 1.

4%N

S

Fem

ales

:Lu

ng (a

lveo

lar/

bron

chio

lar a

deno

mas

or

carc

inom

as)–

4/

46 in

con

trol

s, 7/

45 fe

d 0.

7%, 4

/47

fed

1.4%

NS

Hae

mat

opoi

etic

syst

em (l

euka

emia

or m

alig

nant

ly

mph

oma)

– 5/

48 in

con

trol

s, 6/

45 fe

d 0.

7%, 5

/47

fed

1.4%

NS

Live

r (he

pato

cellu

lar c

arci

nom

as)–

1/

47 in

con

trol

s, 2/

45 fe

d 0.

7%; 3

/47

fed

1.4%

NS

IARC MONOGRAPHS – 100A

390

Spec

ies,

str

ain

(sex

) D

urat

ion

Ref

eren

ce

Rou

te

Dos

ing

regi

men

A

nim

als/

grou

p at

sta

rt

Inci

denc

e of

tum

ours

Sign

ificanc

eC

omm

ents

Mou

se, C

57BL

/6

(M, F

) 75

–80 

wk

Mac

klin

& S

zot

(198

0)

Feed

D

iets

con

tain

ing

aspi

rin,

phe

nace

tin a

nd

caffe

ine,

sing

le o

r in

com

bina

tion,

for 7

5–80

 wk.

G

roup

1: 6

96 m

g/kg

bw

/d a

spir

in-p

hena

cetin

-ca

ffein

e G

roup

2: 6

93 m

g/kg

bw

/d a

spir

in-p

hena

cetin

G

roup

3: 3

21 m

g/kg

bw

/d p

hena

cetin

-caff

eine

G

roup

4: 7

54 m

g/kg

bw

/d p

hena

cetin

G

roup

5: 2

68 m

g/kg

bw

/d p

hena

cetin

G

roup

6: n

one

(con

trol

s)

40 m

ales

and

40

fem

ales

/gro

up

No

tum

ours

rela

ted

to tr

eatm

ent r

epor

ted

The

stud

y w

as li

mite

d by

the

limite

d ex

tent

of

hist

olog

ical

exa

min

atio

n.

Ratio

of t

he c

ompo

nent

s of

the

com

bina

tions

was

: as

piri

n, 7

; phe

nace

tin, 5

; ca

ffein

e, 1

Rat,

F344

(M, F

) 11

3 w

k N

CI (

1978

)

Feed

0,

0.7

or 1

.4%

of a

mix

ture

of a

spir

in,

phen

acet

in a

nd c

affei

ne (5

0:46

:4) f

or u

p to

78

 wk,

obs

erve

d fo

r an

addi

tiona

l 34–

35 w

k 50

/gro

up

Mal

es:

Pitu

itary

gla

nd (a

deno

mas

or c

arci

nom

as)–

8/

47 in

con

trol

s, 18

/47

fed

0.7%

, 12/

44 fe

d 1.

4%P 

= 0.

018

for

low

dos

e A

dren

al g

land

(phe

ochr

omoc

ytom

as)–

7/

47 in

con

trol

s, 17

/49

fed

0.7%

, 9/4

8 fe

d 1.

4%P 

= 0.

022

for

low

dos

eFe

mal

es:

One

tran

sitio

nal c

ell c

arci

nom

a of

the

urin

ary

blad

der (

low

dos

e)N

S

One

tran

sitio

nal c

ell c

arci

nom

a of

the

urin

ary

blad

der (

high

dos

e)N

S

One

tran

sitio

nal c

ell p

apill

oma

of th

e ur

inar

y bl

adde

r (hi

gh d

ose)

NS

One

tubu

lar c

ell a

deno

carc

inom

a of

the

kidn

ey

(low

dos

e) [a

lso o

ne in

low

-dos

e m

ales

]N

S

No

urin

ary

syst

em tu

mou

rs in

con

trol

fem

ales

Tabl

e 3.

1 (c

ontin

ued)

Phenacetin

391

Spec

ies,

str

ain

(sex

) D

urat

ion

Ref

eren

ce

Rou

te

Dos

ing

regi

men

A

nim

als/

grou

p at

sta

rt

Inci

denc

e of

tum

ours

Sign

ificanc

eC

omm

ents

Rat,

Spra

gue-

Daw

ley

(M)

117 

wk

Joha

nsso

n (1

981)

Feed

G

roup

1: 0

.5%

phe

nace

tin

Gro

up 2

: 0.5

% p

hena

zone

G

roup

3: 0

.1% c

affei

ne

Gro

up 4

: 0.5

% p

hena

cetin

+ 0.

5% p

hena

zone

+ 0.

1% c

affei

ne

Gro

up 5

: 0.5

% p

hena

cetin

+ 0.

5% p

hena

zone

G

roup

6: 0

.5%

phe

nace

tin

0.1%

caff

eine

G

roup

7: a

ceta

min

ophe

n G

roup

8: n

one

(con

trol

s)

30/g

roup

Kid

ney

Rena

l cel

lRe

nal p

elvi

sG

roup

1: 4

/29

1/29

[P =

 0.0

24]a

Gro

up 2

: 0/2

94/

29G

roup

3: 0

/28

0/28

Gro

up 4

: 2/3

04/

30[P

 = 0

.012

]a

Gro

up 5

: 7/2

93/

29[P

 = 0

.003

]a

Gro

up 6

: 2/2

91/

29G

roup

7: 0

/30

0/30

Gro

up 8

: 0/3

00/

30U

rina

ry b

ladd

erG

roup

1: 5

/29

Gro

up 2

: 5/2

9G

roup

3: 0

/29

Gro

up 4

: 1/3

0G

roup

5: 4

/29

Gro

up 6

: 4/2

9G

roup

7: 4

/30

Gro

up 8

: 2/3

0Li

ver (

hepa

tom

as)

Gro

up 1

: 0/2

9G

roup

2: 0

/29

Gro

up 3

: 0/2

9G

roup

4: 1

4/30

[P <

 0.0

01]

Gro

up 5

: 0/2

9G

roup

6: 0

/29

Gro

up 7

: 0/2

9G

roup

8: 0

/29

Tabl

e 3.

1 (c

ontin

ued)

IARC MONOGRAPHS – 100A

392

Spec

ies,

str

ain

(sex

) D

urat

ion

Ref

eren

ce

Rou

te

Dos

ing

regi

men

A

nim

als/

grou

p at

sta

rt

Inci

denc

e of

tum

ours

Sign

ificanc

eC

omm

ents

Phen

acet

in a

lone

Mou

se, B

6C3F

1 (M

, F)

110 

wk

Nak

anis

hi e

t al.

(198

2)

Feed

1.

25%

or 0

.6%

phe

nace

tin fo

r 102

 wk,

obs

erve

d fo

r add

ition

al 8

 wk

52/g

roup

50

/sex

as u

ntre

ated

con

trol

s

Kid

ney

tum

ours

:A

deno

mas

–M

32/

48 (1

.25%

dos

e), 1

1/48

(0

.6%

dos

e), 0

/48

(con

trol

s)

F 0/

48, 0

/48,

0/4

8

P < 

0.01

(low

an

d hi

gh d

ose)

Car

cino

mas

–M

14/

48, 1

/48,

0/4

8P

< 0.

01 (h

igh

dose

)F

1/48

, 0/4

8, 0

/48

Uri

nary

bla

dder

:H

yper

plas

ia–

M 7

/48,

1/4

8, 0

/48

P <

0.05

(hig

h do

se)

F 7/

48, 0

/48,

0/4

8P

< 0.

05 (h

igh

dose

)C

arci

nom

as–

M 0

/48,

0/4

8, 0

/48

F 2/

48, 0

/48,

0/4

8

Tabl

e 3.

1 (c

ontin

ued)

Phenacetin

393

Spec

ies,

str

ain

(sex

) D

urat

ion

Ref

eren

ce

Rou

te

Dos

ing

regi

men

A

nim

als/

grou

p at

sta

rt

Inci

denc

e of

tum

ours

Sign

ificanc

eC

omm

ents

Rat,

BDI a

nd

BDII

I 31

 mo

Schm

ähl &

Rei

ter

(195

4)

Feed

40

–50 

mg

phen

acet

in fo

r at l

east

770

d

30/t

reat

men

t gro

up

No

tum

ours

rela

ted

to tr

eatm

ent o

bser

ved

Info

rmat

ion

for c

ontr

ols

and

othe

r exp

erim

enta

l de

tails

lack

ing;

sex

NR

Rats

, Spr

ague

-D

awle

y (M

, F),

9 w

k Is

aka

et a

l. (1

979)

Feed

2.

5% o

r 1.2

5% p

hena

cetin

for 1

8 m

o, o

bser

ved

for a

n ad

ditio

nal 6

 mo

50/s

ex/g

roup

65

/sex

as u

ntre

ated

con

trol

s

Nas

al c

avit

y tu

mou

rs:

Tum

ours

obs

erve

d in

the

high

dos

e gr

oups

wer

e m

ainl

y m

alig

nant

M–1

6/27

(hig

h do

se),

16/2

2 (lo

w d

ose)

, 0/

19 (c

ontr

ols)

[P <

 0.0

1;

P < 

0.01

]F–

7/27

, 6/2

5, 0

/25

[P <

 0.0

1;

P < 

0.01

]U

rina

ry tr

act t

umou

rs:

M–1

3/27

, 1/2

2, 0

/19

[P <

 0.0

1; N

S]F–

4/27

, 0/2

5, 0

/25

[NS;

NS]

Rats

, Spr

ague

-D

awle

y (F

), 9 

wk

110 

wk

Joha

nsso

n &

A

nger

vall

(197

6)

Feed

0%

or 0

.6%

phe

nace

tin fo

r 110

 wk

30/g

roup

Brea

st (a

deno

carc

inom

as):

5/30

in tr

eate

d gr

oup,

1/

30 in

con

trol

sN

S

Ear d

uct (

squa

mou

s cel

l car

cino

mas

): 4/

30 in

tr

eate

d gr

oup,

0/3

0 in

con

trol

sN

S

a whe

n k

idne

y tu

mou

rs w

ere

com

bine

dbw

, bod

y w

eigh

t; d,

day

or d

ays;

F, fe

mal

e; m

o, m

onth

or m

onth

s; M

, mal

e; N

R, n

ot re

port

ed; N

S, n

ot si

gnifi

cant

; wk,

wee

k or

wee

ks; y

r, ye

ar o

r yea

rs

Tabl

e 3.

1 (c

ontin

ued)

IARC MONOGRAPHS – 100A

4. Other Relevant Data

4.1 Absorption, distribution, excretion, and metabolism

4.1.1 Humans

After oral administration of phenacetin, N-acetyl-p-aminophenol, either conjugated or free, is the major metabolite found in urine. Small amounts of 2-hydroxyphenacetin, 3-[(5-acetamido-2-hydroxyphenyl)thio]alanine, S-(1-acetamido-4-hydroxyphenyl)cysteine, 3-methyl-thio-4-hydroxy-acetanilide, and N-hydroxyphenacetin are also detected.

Urinary excretion of 2-hydroxyphenacetin, N-acetyl-p-aminophenol and their conjugates is decreased when phenacetin is administered in combination with aspirin, caffeine, and codeine (Gault et al., 1972)

4.1.2 Experimental systems

Metabolic pathways for phenacetin involve de-ethylation, N-deacetylation, and ring hydroxylation. The main route, as shown in rats, is oxidative de-ethylation, forming N-acetyl-p-aminophenol, which is excreted in the urine as the sulfate or as the glucuronide (Dubach & Raaflaub, 1969). Metabolism by the second pathway, N-deacetylation, is greatest in rats (21% of the dose), and least in guinea-pigs and rabbits (7 and 4% of the dose, respectively) (Smith & Timbrell, 1974). p-Phenetidine, resulting from N-deacetylation, can be converted to 2-hydroxy-para-phenetidine, which in rats is excreted as the sulfate in increasing amounts with increasing doses of phenacetin (Dubach & Raaflaub, 1969).

Other metabolites identified in the urine of experimental animals are 2-hydroxyphen-acetin, 3-[(5-acetamido-2-hydroxyphenyl)thio]alanine, 3-methylthio-4-hydroxyacetanilide, 2-hydroxyacetophenetidine glucuronide,

4-acetaminophenoxyacetic acid, 4-hydroxy-3-methylthioacetanilide, and N-hydroxy-phenacetin (IARC, 1980). Intestinal microflora in rats have been shown to deconjugate the metabolite N-acetyl-p-aminophenyl glucu-ronide, excreted partly in bile, to N-acetyl-p-aminophenol (Smith & Griffiths, 1976).

Evidence that phenacetin is N-hydroxylated by a cytochrome P-450 mono-oxygenase-catalysed reaction has been demonstrated in vitro with hamster and rabbit liver microsomes (Hinson & Mitchell, 1976; Fischbach et al., 1977).

Using rat liver preparations, Mulder et al. (1977) demonstrated the formation of N-O-glucuronide and N-O-sulfate conjugates of N-hydroxyphenacetin.

In rats treated with 3-methylcholanthrene or benzo[a]pyrene or exposed to cigarette smoke, an increased rate of O-de-ethylation of phen-acetin to N-acetyl-p-aminophenol in the lung and intestine was observed (Welch et al., 1972; Kuntzman et al., 1977).

4.2 Genetic and related effects

4.2.1 Humans

In 29 TP53 mutations found in 89 renal pelvic carcinomas, the incidence and type of mutations did not differ significantly between patients with a history of phenacetin abuse, smoking or neither of these habits, and thus do not reflect a mutagenic effect of exposure to phenacetin and/or smoking in the renal pelvis (Bringuier et al., 1998). No other data were available to the Working Group on the genetic and related effects of phenacetin in humans.

4.2.2 Experimental systems

The previous IARC Monograph states that the results of studies on the induction of chromo-somal aberrations, sister chromatid exchange and micronuclei in rodents treated with phenacetin

394

Phenacetin

in vivo were equivocal (IARC, 1987a). More recently, several studies have provided addi-tional evidence that phenacetin can induce chro-mosomal alterations or DNA damage in both target and non-target tissues. Treatment of mice either orally or via intraperitoneal injection with high doses of phenacetin results in increases in micronuclei in the bone-marrow erythrocytes (Hayashi et al., 1989; Sutou et al., 1990). Similarly in rats, daily oral phenacetin treatment for 2 or 14  days increases the frequency of micronuclei in bone-marrow cells, and in peripheral blood (Asanami et al., 1995). In rodents treated with phenacetin, increased DNA damage is detected in the kidney of mice 2–3 hours after treatment, and in the urinary bladder of rats after 20 hours of exposure (Sasaki et al., 1997; Sekihashi et al., 2001; Robbiano et al., 2002). Phenacetin induces cell proliferation in the urothelium of the kidney, the bladder, the renal pelvis (Johansson et al., 1989), and DNA synthesis in the nasal respira-tory and olfactory mucosa of rats (Bogdanffy et al., 1989). Phenacetin also induces chromo-somal aberrations in Chinese hamster cells in vitro and DNA strand breaks in rat and human cells from the urinary bladder in vitro but not in rat hepatocytes after exposure in vivo (IARC, 1987a; Robbiano et al., 2002). In rat kidney cells, a mixture of aspirin, phenacetin and caffeine as well as phenacetin-alone did not induce micro-nuclei, but the metabolite N-hydroxyphenacetin was found to induce micronuclei (Dunn et al., 1987). Phenacetin does not induce sex-linked recessive lethal mutations in Drosophila, and is not mutagenic in mouse embryo cells, but was found to induce a small number of transformed foci (IARC, 1987a; Patierno et al., 1989).

Phenacetin is mutagenic to bacteria when tested in the presence of a metabolic system derived from hamster or rat liver but not mouse (IARC, 1987a; Nohmi et al., 1987). The urine from phenacetin-treated Chinese hamsters, but not that from rats, is mutagenic to bacteria (IARC, 1987a). Administration of phenacetin

(0.75%) mixed in the feed of mice deficient in nucleotide-excision repair results in an observed increased mutation frequency in a Lac Z reporter gene in the kidney (Luijten et al., 2006).

While there is evidence of genetic damage caused by phenacetin in various experimental systems, similar data are not available in humans.

5. Evaluation

There is sufficient evidence in humans for the carcinogenicity of analgesic mixtures containing phenacetin. Analgesic mixtures containing phenacetin cause cancer of the renal pelvis, and of the ureter.

There is limited evidence in experimental animals for the carcinogenicity of analgesic mixtures containing phenacetin.

There is sufficient evidence in humans for the carcinogenicity of phenacetin. Phenacetin causes cancer of the renal pelvis, and of the ureter.

There is sufficient evidence in experimental animals for the carcinogenicity of phenacetin.

Analgesic mixtures containing phenacetin are carcinogenic to humans (Group 1).

Phenacetin is carcinogenic to humans (Group 1).

For the overall evaluation of phenacetin, the Working Group took into consideration that tumours of the renal pelvis and ureter are not known to result from the other components of the analgesic mixtures used in most countries; namely, aspirin, codeine phosphate, and caffeine.

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